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首页> 外文期刊>Cellular immunology >CD4(+) T cells engineered with FVIII-CAR and murine Foxp3 suppress anti-factor VIII immune responses in hemophilia a mice
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CD4(+) T cells engineered with FVIII-CAR and murine Foxp3 suppress anti-factor VIII immune responses in hemophilia a mice

机译：用FVIII-CAR和鼠FOXP3设计的CD4（+）T细胞抑制血友病中的抗因子VIII免疫应答

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Although protein replacement therapy provides effective treatment for hemophilia A patients, about a third of severe patients develop neutralizing inhibitor antibodies to factor VIII. Adoptive transfer of regulatory T cells (Tregs) has shown promise in treating unwanted immune responses. In previous studies, transferred polyclonal Tregs ameliorated the anti-factor VIII immune responses in hemophilia A mice. In addition, factor VIII-primed Tregs demonstrated increased suppressive function. However, antigen-specific Tregs are a small fraction of the total lymphocyte population. To generate large numbers of factor VIII-specific Tregs, the more abundant murine primary CD4+ T cells were lentivirally transduced ex vivo to express Foxp3 and a chimeric antigen receptor specific to factor VIII (F8CAR). Transduced cells significantly inhibited the proliferation of factor VIII-specific effector T cells in suppression assays. To monitor the suppressive function of the transduced chimeric antigen receptor expressing T cells in vivo, engineered CD4+ CD25(+) Foxp3(+) F8CAR-Tregs were sorted and adoptively transferred into hemophilia A mice that are treated with hydrodynamically injected factor VIII plasmid. Mice receiving engineered F8CAR-Tregs showed maintenance of factor VIII clotting activity and did not develop antifactor VIII inhibitors, while control CD4(+) T cell or PBS recipient mice developed inhibitors and had a sharp decrease in factor VIII activity. These results show that CD4 cells lentivirally transduced to express Foxp3 and F8CAR can promote factor VIII tolerance in a murine model. With further development and testing, this approach could potentially be applied to human hemophilia patients.
机译：虽然蛋白质替代疗法为血友病A患者提供了有效的治疗，但约三分之一的重症患者产生了针对因子VIII的中和抑制剂抗体。过继转移调节性T细胞（Tregs）在治疗不必要的免疫反应方面显示出了希望。在之前的研究中，转移的多克隆Tregs改善了血友病A小鼠的抗VIII因子免疫反应。此外，因子VIII启动的Tregs显示出更强的抑制功能。然而，抗原特异性Treg只占淋巴细胞总数的一小部分。为了产生大量因子VIII特异性Treg，体外慢病毒转导更丰富的小鼠原代CD4+T细胞，以表达Foxp3和因子VIII特异性嵌合抗原受体（F8CAR）。在抑制实验中，转导细胞显著抑制因子VIII特异性效应T细胞的增殖。为了在体内监测表达嵌合抗原受体的转基因T细胞的抑制功能，对工程化的CD4+CD25（+）Foxp3（+）F8CAR-Tregs进行分类并过继转移到血友病A小鼠体内，该小鼠经流体动力注射因子VIII质粒治疗。接受工程化F8CAR-Tregs的小鼠显示出凝血因子VIII活性的维持，并且没有开发出抗凝血因子VIII抑制剂，而对照CD4（+）T细胞或PBS受体小鼠开发出抑制剂，并且VIII因子活性急剧降低。这些结果表明，在小鼠模型中，慢病毒转导表达Foxp3和F8CAR的CD4细胞可以促进因子VIII耐受。随着进一步的开发和测试，这种方法有可能应用于人类血友病患者。

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